Prostate cancer is a very important health problem in the United States. It will be diagnosed in approximately 350,000 American men and will cause approximately 42,000 deaths in 1998. Genetic mutations are known to cause a variety of human cancers however the molecular genetic defects leading to prostate carcinoma are still unidentified despite the detection of a variety of chromosomal abnormalities in prostate tumors. The most commonly observed abnormality is a deletion at 8p12-22, suggesting that a gene(s) important for prostate carcinogenesis is located within this chromosomal region. Evidence is rapidly accumulating that inappropriate activity of developmental regulators can result in malignant transformation. A recently discovered factor, Nkx3.1, possesses may properties expected of such a regulator: it is a homeodomain protein, a class of transcription factors critically involved in many developmental processes; it is expressed in developing and mature prostate, and its chromosomal location, 8p21, suggests it is lost in many prostate tumors. We therefore plan to investigate whether Nkx3.1 regulates prostate development and whether loss of Nkx3.1 results in differentiation of prostate cells, hence contributing to prostate carcinogenesis. The capacity of Nkx3.1 to drive prostate-specific differentiation in vitro, and its effects on growth, patterns of gene expression, and tumorigenicity of prostate carcinoma cell lines will be investigated. The Nkx3.1 in human prostate tumors will be examined using immunohistochemistry, and microdissected prostate tumor specimens will be used to search for Nkx3.1 mutations and/or evidence of hypermethylation. Specific cell types expressing Nkx3.1 in developing and mature urogenital tract will be identified using immunohistochemistry. Gene targeting using the Cre/lox recombination system will be used to generate mice that suffer sudden loss of Nkx3.1 function in adulthood. These mice will be examined for evidence of prostate hyperplasia and neoplasia, and for functional and morphological alterations. In summary, our work will determine whether loss of Nkx3.1 function is a major cause of prostate cancer.